1-amino-alkylcyclohexane derivatives for the treatment of mast cell mediated diseases

ABSTRACT

The present invention relates to the treatment of an individual afflicted with mast cell mediated diseases comprising administering to the individual an effective amount of a 1-amino-alkylcyclohexane derivative.

FIELD OF THE INVENTION

The present invention relates to the treatment of an individualafflicted with mast cell mediated diseases, comprising administering tothe individual an effective amount of a 1-amino-alkylcyclohexanederivative.

BACKGROUND OF THE INVENTION

This invention relates to methods of treating patients afflicted withmast cell mediated diseases, including urticaria, atopic dermatitis,psoriasis, pruritus, asthma, rhinitis, mastocytosis, conjunctivitis andkeratoconjunctivitis.

Mast cells (MC) and blood basophils are crucial components of theacquired and innate human immune system. The different subtypes arefound in almost all tissues, most abundantly in the skin and therespiratory and gastrointestinal tract. Mast cells are the primaryeffector cells in immunoglobulin E (IgE) mediated inflammatory reactionsand are involved in maintenance of skin and mucosal homeostasis as wellas in neurohumoral interactions associated with various inflammatoryprocesses, such as allergic inflammation. Mast cells are involved incertain inflammatory dermatologic diseases, such as urticaria, cutaneousmastocytosis, atopic dermatitis and psoriasis and in the polyetiologicalpruritus. Mast cells are also involved in extracutaneous diseases suchas rhinitis, systemic mastocytosis, allergic and non-allergic asthmabronchiale, conjunctivitis and keratoconjunctivitis. A key event in mastcell triggered inflammatory processes is mast cell degranulation, inwhich an extensive mixture of different cytokines and neurotransmitters(such as serotonin and/or histamine) is delivered to surrounding tissue.

Mast cells differentiate from bone-marrow derived CD34+ myeloicprecursor cells. After leaving the blood stream, these precursorsdifferentiate under the influence of local growth factors to maturetissue mast cells (Wedemeyer et al. 2000, Curr Opin Immunol. 2000;12(6):624-31). Mast cells reside in close proximity to vessels, nervesand surface epithelium. In human skin, the highest density of mast cellscan be found around hair follicles, sweat glands, sebaceous glands andcapillaries of the stratum papillare (Toruniowa, Jablonska 1988).Anatomical and functional interactions between mast cells and peripheralnerves have also been reported (Bienenstock et al. 1987 Int Arch AllergyAppl Immunol 82: 238-43; Naukkarinen et al. 1996. J Pathol. 1996;180(2):200-5).

Mast cells have a diameter of 9-11 μm and are characterized by numerousbasophilic granules. Mast cells are important effectors of allergicreactions. Mast cells play an important role in many physiological andpathological processes because of their susceptibility to numerousactivating stimuli and their ability to release a plethora of differentmediators. Mast cells have been implicated in numerous skin and mucosaldiseases, including inflammation, hypersensitivity, and tissue repair(Benoist and Mathis, 2002; Nature. 2002; 420(6917):875-8). Mast cellscommunicate with sensory nerves and blood vessels via histamine release,thereby regulating neurogenic inflammation and pruritus (Steinhoff etal., 2003, Arch Dermatol. 2003; 139(11):1479-88.

Urticaria is a dermatological disease which involves activated mastcells. In urticarial lesions, mast cells are degranulated, and theeffects of vasoactive mast cell components like histamine dominate theclinical symptoms. Many patients suffer from hives, pruritus and softtissue swelling. The causes of urticaria are numerous, indeed, there aredifferent entities ranging from acute urticaria as symptom of anallergic anaphylaxis, e.g. after ingestion of peanuts in a peanutallergic patient. Type I allergies are unique in this context because aspecific mechanism and a specific agent are necessary to induce thiseffect. In other forms of urticaria, either specific triggers areunknown or do not exist (Maurer, et al., Hautarzt. 2003; 54(2):138-43).Urticaria may also occur in association with a viral or bacterialinfection. Neuroendocrine factors are also known to be involved in theonset of e.g. adrenergic or cholinergic urticaria, both of which occurafter physical exercise (Maurer et al., Hautarzt. 2004; 55(4):350-6;Mlynek et al., Curr Opin Allergy Clin Immunol. 2008; 8(5):433-7).

Typical treatment of urticaria involves blockage of histamine receptorsof the H1 and, less commonly, the H2 subtype. Other pharmacologicalagents (such as cromoclycine acid or montelukast) have been reported to“stabilize” mast cell membranes; however, these agents have also beenreported as less effective in the treatment of urticaria. Moreover, insevere cases, steroids need to be administered to prevent the onset ofanaphylaxis.

One of the main drawbacks associated with current treatments forurticaria is the low efficacy of antihistamines in severe,life-threatening forms of acute urticaria and in the treatment ofchronic forms of urticaria that do not have a determinable cause and aretherefore referred to as idiopathic. Some patients suffer fromidiopathic forms of urticaria for several years and have a stronglyreduced quality of life (Mlynek et al., Curr Opin Allergy Clin Immunol.2008; 8(5):433-7).

Psoriasis is a polygenetic hereditary multifactorial inflammatory skindisease of complex pathogenesis, which may be influenced by a number ofenvironmental factors. Despite substantial progress regarding thepathogenetic mechanisms involved in this disease, many factors stillremain unresolved. Mast cells and macrophages are prominent in intialand developing psoriatic lesions, but are also found in stable lesions.Although late events leading to the clinical psoriatic phenotype arewell understood (e.g., involvement of Th1 dominated cytokines leading tothe epidermal psoriatic reaction pattern), early events which mightunravel genetic alterations and crucial pathogenetic checkpoints remainobscure.

Several lines of evidence suggest an involvement of the cholinergicsystem in the pathogenesis of psoriasis. More than 50 years ago aHungarian study group treated psoriasis patients with theanticholinergic substance atropine, based on the assumption that theparasympathetic nervous system must be responsible for an increasedcontent of acetylcholine in the psoriatic lesions thus initiating theonset and mediating the course of the disease (Helmeczi, Dermatologica,1955 110: 439-48). A careful analysis of the patients presented inHelmeczi's study reveals that almost exclusively those patients with“eruptive psoriasis” responded to the oral atropine treatment, whilethose with chronic plaque type psoriasis generally did not. According toseveral histological studies, the first cells that “arrive” in psoriasislesions are mast cells and neutrophilic granulocytes. Indeed mast cellshave been found significantly increased in number especially in guttatepsoriasis and palmoplantar psoriasis (Schubert and Christophers, ArchDermatol Res 1985; 277:352-8; Brody, J Invest Dermatol. 1984 May;82(5):460-4; Naukkarinen et al., J Pathol. 1996 October; 180(2):200-5;Ashenagar et al., Arch Dermatol Res. 2007 February; 298(9):421-6) whilechronic lesions are dominated by lymphocytes and macrophages (GhoreschiK and Röcken M; J Dtsch Dermatol Ges 2003; 1: 524-32).

One study demonstrates a significant increase of mast cells in chronicpsoriasis lesions only in patients complaining of pruritus (Nakamura etal. 2003 Br J Dermatol;149(4):718-30), while other immune cells andcytokines did not show any difference. In addition, mast celldegranulation has been shown to induce ICAM-1 expression in psoriaticepidermis, thus initiating the inflammatory cascade (Ackermann andHarvima, Arch Dermatol Res. 1998 July; 290(7):353-9). There isadditional evidence for a role of mast cells in psoriasis from a mousemodel. The so called flaky mouse (congenic fsn/fsn) shows diffuseepidermal orthokeratotic hyperkeratosis reminding strongly of psoriasis.In this mouse, numerous mast cells are lining up under the epidermis(Sundberg et al., Eur J Immunol 1998 April; 28(4):1379-88). The close“synapse-like” proximity of mast cells with free nerve endingscontaining a plethora of proinflammatory neurotransmitters together withtheir well-documented responsiveness to “stress-hormones” like CRH andurocortin, makes mast cells the ideal target for stress related andneurogenic inflammatory processes (Arck et al., J Mol. Med. 2005;83(5):386-96) which fits well to the clinical association of psoriasiswith emotional stress (Singh et al., J Pharmacol Exp Ther. 1999 March;288(3):1349-56). The physiological function of mast cells has beendiscussed intensely (Maurer et al., Exp Dermatol. 2003 December;12(6):886-910); however, it has been convincingly demonstrated that mastcells are key cells of neuroendocrine inflammatory processes (Arck etal., J Mol. Med. 2005; 83(5):386-96; Siebenhaar, et al., J Allergy ClinImmunol. 2008; 121(4):955-61) that can be stimulated by a great varietyof different stimuli, amongst them, acetylcholine (Fantozzi et al. 1978Nature 273: 473-4).

There are several psoriasis treatment protocols aiming at secretoryproducts of mast cells, in particular histamine. The use of H1-R andH2-R blockers has been suggested and documented in small studies(Kristensen et al., Br J. Dermatol. 1995 December; 133(6):905-8;Petersen et al., Acta Derm Venereol. 1998 May; 78(3):190-3); however,randomized controlled trials did not show significant therapeuticeffects. These results/lack of effect may have been due to using thePASI score and not the psoriasis subtype or acuity as stratificationfactor (Zonneveld et al., J Am Acad Dermatol. 1997 June; 36(6 Pt1):932-4. 7-103).

Several changes in the cholinergic system have been documented inpsoriatic lesions: SLURP-2 is a peptide modulator of nicotiniccholinergic receptors that has been found elevated in psoriatic lesions.SLURP-2 has been shown to inhibit caspase-3 and filaggrin and,therefore, has been suggested to be involved in psoriasis through itsrole in keratinocyte hyperproliferation and/or T celldifferentiation/activation (Tsuji et al., Genomics 2003; 81(1):26-33).

Smoking increases the risk of psoriasis at least in a subset ofpatients. This effect most probably is related to the main cigarettetoxin, nicotine, a ligand of the nicotinic acetylcholine receptor(nAChR) (Arathi et al., Am J Med, 2007, 120 (11): 953-959) also activeat the α10 nAChR present in mast cells. In addition, a special form ofpsoriasis, the pustulosis palmoplantaris (PPP) correlates strongly withsmoking PPP lesions are particularly rich in mast cells expressingacetylcholine esterase (AChE) and granulocytes expressing ChAT and α3nAChR. (Hagforsen et al., Acta Derm Venereol 2002; 82(5):341-6).

Mast cells are also key effector cells in bronchial asthma.Anticholinergic substances acting on the muscarinic acetylcholinereceptor (mAChR) are on the market (tiotropium) for the treatment ofasthma. It has been suggested that there may be an involvement of bothneuronal and non-neuronal derived ACh in lung mucosal inflammation,involving lymphocytes and macrophages, mast cells (Wessler andKirkpatrick, Pulm Pharmacol Ther. 2001; 14(6):423-34). This notion hasimmediate impact on the issue of tobacco-derived nicotine action in lungdiseases on the one hand, and the use of anti-muscarinic drugs inchronic airway diseases on the other hand.

Rhinitis involves inflammation and swelling of the mucous membrane ofthe nose, characterized by a runny nose and stuffiness, and is usuallycaused by the common cold or an allergy.

Allergic rhinitis is the most common cause of rhinitis. It is anextremely common condition, affecting approximately 20% of thepopulation. While allergic rhinitis is not a life-threatening condition,complications can occur and the condition can significantly impairquality of life, which leads to a number of indirect costs. The totaldirect and indirect cost of allergic rhinitis was recently estimated tobe $5.3 billion per year.

Allergic rhinitis involves inflammation of the mucous membranes of thenose, eyes, eustachian tubes, middle ear, sinuses, and pharynx. The noseinvariably is involved, and other organs are affected in certainindividuals. Inflammation of the mucous membranes is characterized by acomplex interaction of inflammatory mediators but ultimately istriggered by an immunoglobulin E (IgE)-mediated response to an extrinsicprotein.

The tendency to develop allergic, or IgE-mediated, reactions toextrinsic allergens (proteins capable of causing an allergic reaction)has a genetic component. In susceptible individuals, exposure to certainforeign proteins leads to allergic sensitization, which is characterizedby the production of specific IgE directed against these proteins. Thisspecific IgE coats the surface of mast cells, which are present in thenasal mucosa. When the specific protein (e.g., a specific pollen grain)is inhaled into the nose, it can bind to the IgE on the mast cells,leading to immediate and delayed release of a number of mediators.

The mediators that are immediately released include histamine, tryptase,chymase, kinins, and heparin. The mast cells quickly synthesize othermediators, including leukotrienes and prostaglandin D2. These mediators,via various interactions, ultimately lead to the symptoms of rhinorrhea(ie, nasal congestion, sneezing, itching, redness, tearing, swelling,ear pressure, postnasal drip). Mucous glands are stimulated, leading toincreased secretions. Vascular permeability is increased, leading toplasma exudation. Vasodilation occurs, leading to congestion andpressure. Sensory nerves are stimulated, leading to sneezing anditching. All of these events can occur in minutes; hence, this reactionis called the early, or immediate, phase of the reaction.

Over 4-8 hours, the above-mentioned mediators, through a complexinterplay of events, lead to the recruitment of other inflammatory cellsto the mucosa, such as neutrophils, eosinophils, lymphocytes, andmacrophages. This results in continued inflammation, termed thelate-phase response. The symptoms of the late-phase response are similarto those of the early phase, but less sneezing and itching and morecongestion and mucus production tend to occur. The late phase maypersist for hours or days.

Atopic dermatitis is a pruritic disease of unknown origin that usuallystarts in early infancy (an adult-onset variant is recognized); it ischaracterized by pruritus, eczematous lesions, xerosis (dry skin), andlichenification (thickening of the skin and an increase in skinmarkings). Atopic dermatitis may be associated with other atopic(immunoglobulin E [IgE]) diseases (e.g., asthma, allergic rhinitis,urticaria, acute allergic reactions to foods). Atopic dermatitis hasenormous morbidity, and the incidence and prevalence appear to beincreasing.

Substantial evidence indicates that genetic factors are important in thedevelopment of atopic dermatitis (AD), but the pathophysiology is stillpoorly understood. Two main hypotheses have been proposed regarding thedevelopment of the inflammatory lesions. The first suggests an immunedysfunction resulting in IgE sensitization and a secondaryepithelial-barrier disturbance. The second proposes a defect inepithelial cells leading to the defective barrier problem, with theimmunological aspects being epiphenomena.

Pruritus is a common manifestation of dermatologic diseases, such asurticaria, atopic dermatitis, and other allergic reactions. Effectivetreatment of pruritus can prevent scratch-induced complications such aslichen simplex chronicus and impetigo.

Pruritus originates within the skin's free nerve endings, which are mostheavily concentrated in the wrists and ankles. The sensation of pruritusis transmitted through C fibers to the dorsal horn of the spinal cordand then to the cerebral cortex via the spinothalamic tract. Pruritusgenerates a spinal reflex response, the scratch, which is as innate as adeep tendon reflex. Regardless of the cause, pruritus often isexacerbated by skin inflammation, dry or hot ambient conditions, skinvasodilation, and psychologic stressors.

Histamine, which is released by mast cells in persons with urticaria andother allergic reactions, is one of the factors classically associatedwith pruritus.

As noted above, there are various disadvantages associated with theavailable treatments for mast cell mediated diseases such as urticaria,atopic dermatitis, psoriasis, pruritus, asthma, rhinitis, mastocytosis,conjunctivitis and keratoconjunctivitis. Thus, a need exists forimproved treatments for urticaria, atopic dermatitis, psoriasis,pruritus, asthma, rhinitis, mastocytosis, conjunctivitis andkeratoconjunctivitis and other mast cell mediated diseases.

1-Amino-alkylcyclohexane derivatives such as neramexane (also known as1-amino-1,3,3,5,5-pentamethylcyclohexane) have been found to be usefulin the therapy of various diseases especially in certain neurologicaldiseases, including Alzheimer's disease and neuropathic pain.1-Amino-alkylcyclohexane derivatives such as neramexane are disclosed indetail in U.S. Pat. Nos. 6,034,134 and 6,071,966, the subject matter ofwhich patents is hereby incorporated by reference. It is believed thatthe therapeutic action of 1-amino-alkylcyclohexanes such as neramexaneis related to the inhibition of the effects of excessive glutamate atthe N-methyl-D-aspartate (NMDA) receptors of nerve cells, for whichreason the compounds are also categorized as NMDA antagonists, or NMDAreceptor antagonists.

Neramexane is also a blocker of the α9α10 nicotinic AcetylcholineReceptor. Neramexane behaves as a non-competitive antagonist. Sinceblockage by neramexane at concentrations higher than 1 mM has beenreported to be only slightly dependent on the membrane potential and hasalso been reported not to modify the rate of desensitization, anadditional mechanism might be involved. (Plazas, Paola V. et al.,European Journal of Pharmacology 2007; 566: 11-19).

SUMMARY OF THE INVENTION

The present invention relates to a method of treating and/or preventingmast cell mediated diseases, such as urticaria, atopic dermatitis,psoriasis, pruritus, asthma, rhinitis, mastocytosis, conjunctivitis, andkeratoconjunctivitis in a subject in need thereof, comprisingadministering to the individual an effective amount of a1-amino-alkylcyclohexane derivative (e.g., neramexane or apharmaceutically acceptable salt thereof such as neramexane mesylate).

The present invention also relates to a method of treating and/orpreventing mast cell mediated diseases, such as food allergies in asubject in need thereof, comprising administering to the individual aneffective amount of a 1-amino-alkylcyclohexane derivative (e.g.,neramexane or a pharmaceutically acceptable salt thereof such asneramexane mesylate).

A further aspect of the invention relates to such a method wherein the1-amino-alkylcyclohexane derivative (e.g., neramexane or apharmaceutically acceptable salt thereof such as neramexane mesylate) isadministered once a day, twice a day (b.i.d.), or three times a day.

A further aspect of the invention relates to such a method wherein the1-amino-alkylcyclohexane derivative (e.g., neramexane or apharmaceutically acceptable salt thereof such as neramexane mesylate) isadministered in an immediate release formulation.

A further aspect of the invention relates to such a method wherein the1-amino-alkylcyclohexane derivative (e.g., neramexane or apharmaceutically acceptable salt thereof such as neramexane mesylate) isadministered in a modified release formulation.

A further aspect of the invention relates to such a method wherein the1-amino-alkylcyclohexane derivative (e.g., neramexane or apharmaceutically acceptable salt thereof such as neramexane mesylate) isadministered in a topical formulation such as a topical rinse off orleave on formulation.

A further aspect of the invention relates to such a method wherein the1-amino-alkylcyclohexane derivative (e.g., neramexane or apharmaceutically acceptable salt thereof such as neramexane mesylate) isadministered in an oral formulation.

A further aspect of the invention relates to such a method wherein the1-amino-alkylcyclohexane derivative (e.g., neramexane or apharmaceutically acceptable salt thereof such as neramexane mesylate) isadministered systemically.

A further aspect of the invention relates to a method of treating and/orpreventing mast cell mediated diseases in a subject in need thereof,comprising administering to the individual an effective amount of a1-amino-alkylcyclohexane derivative (e.g., neramexane or apharmaceutically acceptable salt thereof such as neramexane mesylate)and one or more additional pharmaceutical agents (e.g. anticholinergicsubstances (e.g. mecamylamine, kynurenic acid, d-tubocurarine,hexamethonium, atropine, ipratropium, oxitropium, and tiotropium),antihistamines, (e.g. Diphenhydramine, Loratadine, Desloratadine,Meclizine, Quetiapine, Fexofenadine, Pheniramine, Cetirizine,Promethazine, Cimetidine, Famotidine, Ranitidine, Nizatidine, A-349,821,ABT-239, Ciproxifan, Clobenpropit, Thioperamide, JNJ 7777120,Cromoglicate, Nedocromil), Corticosteroids (e.g. prednisone, cortisone,hydrocortisone), glucocorticoids (e.g. ciclesonide, beclomethasone,budesonide, flunisolide, fluticasone, mometasone, and triamcinolone),Leukotriene modifiers (e.g. montelukast, zafirlukast, pranlukast, andzileuton), Methylxanthines (e.g. theophylline and aminophylline),Omalizumab, Methotrexate and ketotifen) which has been shown to beeffective in treating or preventing mast cell mediated diseases.

A further aspect of the invention relates to such a method wherein the1-amino-alkylcyclohexane derivative (e.g., neramexane or apharmaceutically acceptable salt thereof such as neramexane mesylate)and the additional pharmaceutical agent (e.g. anticholinergic substances(e.g. mecamylamine, kynurenic acid, d-tubocurarine, hexamethonium,atropine, ipratropium, oxitropium, and tiotropium), antihistamines,(e.g. Diphenhydramine, Loratadine, Desloratadine, Meclizine, Quetiapine,Fexofenadine, Pheniramine, Cetirizine, Promethazine, Cimetidine,Famotidine, Ranitidine, Nizatidine, A-349,821, ABT-239, Ciproxifan,Clobenpropit, Thioperamide, JNJ 7777120, Cromoglicate, Nedocromil),Corticosteroids (e.g. prednisone, cortisone, hydrocortisone),glucocorticoids (e.g. ciclesonide, beclomethasone, budesonide,flunisolide, fluticasone, mometasone, and triamcinolone), Leukotrienemodifiers (e.g. montelukast, zafirlukast, pranlukast, and zileuton),Methylxanthines (e.g. theophylline and aminophylline), Omalizumab,Methotrexate and ketotifen) are administered conjointly.

A further aspect of the invention relates to such a method wherein the1-amino-alkylcyclohexane derivative (e.g., neramexane or apharmaceutically acceptable salt thereof such as neramexane mesylate)and the additional pharmaceutical agent (e.g. anticholinergic substances(e.g. mecamylamine, kynurenic acid, d-tubocurarine, hexamethonium,atropine, ipratropium, oxitropium, and tiotropium), antihistamines,(e.g. Diphenhydramine, Loratadine, Desloratadine, Meclizine, Quetiapine,Fexofenadine, Pheniramine, Cetirizine, Promethazine, Cimetidine,Famotidine, Ranitidine, Nizatidine, A-349,821, ABT-239, Ciproxifan,Clobenpropit, Thioperamide, JNJ 7777120, Cromoglicate, Nedocromil),Corticosteroids (e.g. prednisone, cortisone, hydrocortisone),glucocorticoids (e.g. ciclesonide, beclomethasone, budesonide,flunisolide, fluticasone, mometasone, and triamcinolone), Leukotrienemodifiers (e.g. montelukast, zafirlukast, pranlukast, and zileuton),Methylxanthines (e.g. theophylline and aminophylline), Omalizumab,Methotrexate and ketotifen) are administered in a single formulation.

A further aspect of the invention relates to such a method wherein the1-amino-alkylcyclohexane derivative (e.g., neramexane or apharmaceutically acceptable salt thereof such as neramexane mesylate)and the additional pharmaceutical agent (e.g. anticholinergic substances(e.g. mecamylamine, kynurenic acid, d-tubocurarine, hexamethonium,atropine, ipratropium, oxitropium, and tiotropium), antihistamines,(e.g. Diphenhydramine, Loratadine, Desloratadine, Meclizine, Quetiapine,Fexofenadine, Pheniramine, Cetirizine, Promethazine, Cimetidine,Famotidine, Ranitidine, Nizatidine, A-349,821, ABT-239, Ciproxifan,Clobenpropit, Thioperamide, JNJ 7777120, Cromoglicate, Nedocromil),Corticosteroids (e.g. prednisone, cortisone, hydrocortisone),glucocorticoids (e.g. ciclesonide, beclomethasone, budesonide,flunisolide, fluticasone, mometasone, and triamcinolone), Leukotrienemodifiers (e.g. montelukast, zafirlukast, pranlukast, and zileuton),Methylxanthines (e.g. theophylline and aminophylline), Omalizumab,Methotrexate and ketotifen) are administered in a topical formulationsuch as topical rinse-off or leave-on formulation.

A further aspect of the invention relates to such a method wherein the1-amino-alkylcyclohexane derivative (e.g., neramexane or apharmaceutically acceptable salt thereof such as neramexane mesylate)and the additional pharmaceutical agent (e.g. anticholinergic substances(e.g. mecamylamine, kynurenic acid, d-tubocurarine, hexamethonium,atropine, ipratropium, oxitropium, and tiotropium), antihistamines,(e.g. Diphenhydramine, Loratadine, Desloratadine, Meclizine, Quetiapine,Fexofenadine, Pheniramine, Cetirizine, Promethazine, Cimetidine,Famotidine, Ranitidine, Nizatidine, A-349,821, ABT-239, Ciproxifan,Clobenpropit, Thioperamide, JNJ 7777120, Cromoglicate, Nedocromil),Corticosteroids (e.g. prednisone, cortisone, hydrocortisone),glucocorticoids (e.g. ciclesonide, beclomethasone, budesonide,flunisolide, fluticasone, mometasone, and triamcinolone), Leukotrienemodifiers (e.g. montelukast, zafirlukast, pranlukast, and zileuton),Methylxanthines (e.g. theophylline and aminophylline), Omalizumab,Methotrexate and ketotifen) is administered systemically.

A further aspect of the invention relates to such a method wherein the1-amino-alkylcyclohexane derivative (e.g., neramexane or apharmaceutically acceptable salt thereof such as neramexane mesylate)and the additional pharmaceutical agent (e.g. anticholinergic substances(e.g. mecamylamine, kynurenic acid, d-tubocurarine, hexamethonium,atropine, ipratropium, oxitropium, and tiotropium), antihistamines,(e.g. Diphenhydramine, Loratadine, Desloratadine, Meclizine, Quetiapine,Fexofenadine, Pheniramine, Cetirizine, Promethazine, Cimetidine,Famotidine, Ranitidine, Nizatidine, A-349,821, ABT-239, Ciproxifan,Clobenpropit, Thioperamide, JNJ 7777120, Cromoglicate, Nedocromil),Corticosteroids (e.g. prednisone, cortisone, hydrocortisone),glucocorticoids (e.g. ciclesonide, beclomethasone, budesonide,flunisolide, fluticasone, mometasone, and triamcinolone), Leukotrienemodifiers (e.g. montelukast, zafirlukast, pranlukast, and zileuton),Methylxanthines (e.g. theophylline and aminophylline), Omalizumab,Methotrexate and ketotifen) are administered in an oral formulation.

A further aspect of the invention relates to a 1-amino-alkylcyclohexanederivative (e.g., neramexane or a pharmaceutically acceptable saltthereof such as neramexane mesylate) for the treatment of an individualafflicted with mast cell mediated diseases such as urticaria, atopicdermatitis, psoriasis, pruritus, asthma, rhinitis, mastocytosis,conjunctivitis, and keratoconjunctivitis.

A further aspect of the invention relates to a 1-amino-alkylcyclohexanederivative (e.g., neramexane or a pharmaceutically acceptable saltthereof such as neramexane mesylate) for the treatment of an individualafflicted with mast cell mediated diseases such as food allergies.

A further aspect of the invention relates to the use of a1-amino-alkylcyclohexane derivative (e.g., neramexane or apharmaceutically acceptable salt thereof such as neramexane mesylate)for the manufacture of a medicament for treatment of an individualafflicted with mast cell mediated diseases such as urticaria, atopicdermatitis, psoriasis, pruritus, asthma, rhinitis, mastocytosis,conjunctivitis, and keratoconjunctivitis.

A further aspect of the invention relates to the use of a1-amino-alkylcyclohexane derivative (e.g., neramexane or apharmaceutically acceptable salt thereof such as neramexane mesylate)for the manufacture of a medicament for treatment of an individualafflicted with mast cell mediated diseases such as food allergies.

A further aspect of the invention relates to the above-definedderivative or use wherein neramexane mesylate is administered in a rangefrom about 5 mg to about 150 mg/day, or neramexane mesylate isadministered in a range from about 5 mg to about 100 mg/day, orneramexane mesylate is administered in a range from about 5 mg to about75 mg/day, or wherein neramexane mesylate is administered at about 50mg/day or wherein neramexane mesylate is administered at about 75 mg/dayfor example in an oral formulation.

A further aspect of the invention relates to the above-definedderivative or use wherein the 1-amino-alkylcyclohexane derivative (e.g.,neramexane or a pharmaceutically acceptable salt thereof such asneramexane mesylate) is administered once a day, twice a day (b.i.d.),or three times a day.

A further aspect of the invention relates to the above-definedderivative or use wherein the 1-amino-alkylcyclohexane derivative (e.g.,neramexane or a pharmaceutically acceptable salt thereof such asneramexane mesylate) is administered in an immediate release formulationor a modified release formulation.

A further aspect of the invention relates to the above-definedderivative or use wherein the 1-amino-alkylcyclohexane derivative (e.g.,neramexane or a pharmaceutically acceptable salt thereof such asneramexane mesylate) is administered in a topical formulation, such as atopical rinse off or leave on formulation.

A further aspect of the invention relates to the above-definedderivative or use wherein the 1-amino-alkylcyclohexane derivative (e.g.,neramexane or a pharmaceutically acceptable salt thereof such asneramexane mesylate) is administered in an oral formulation.

A further aspect of the invention relates to the above-definedderivative or use wherein the 1-amino-alkylcyclohexane derivative (e.g.,neramexane or a pharmaceutically acceptable salt thereof such asneramexane mesylate) is administered systemically.

A further aspect of the invention relates to the above-definedderivative or use wherein at least one additional pharmaceutical agent(e.g. anticholinergic substances (e.g. mecamylamine, kynurenic acid,d-tubocurarine, hexamethonium, atropine, ipratropium, oxitropium, andtiotropium), antihistamines, (e.g. Diphenhydramine, Loratadine,Desloratadine, Meclizine, Quetiapine, Fexofenadine, Pheniramine,Cetirizine, Promethazine, Cimetidine, Famotidine, Ranitidine,Nizatidine, A-349,821, ABT-239, Ciproxifan, Clobenpropit, Thioperamide,JNJ 7777120, Cromoglicate, Nedocromil), Corticosteroids (e.g.prednisone, cortisone, hydrocortisone), glucocorticoids (e.g.ciclesonide, beclomethasone, budesonide, flunisolide, fluticasone,mometasone, and triamcinolone), Leukotriene modifiers (e.g. montelukast,zafirlukast, pranlukast, and zileuton), Methylxanthines (e.g.theophylline and aminophylline), Omalizumab, Methotrexate and ketotifen)which has been shown to be effective in treating or preventing mast cellmediated diseases is administered.

A further aspect of the invention relates to the above-definedderivative or use wherein the 1-amino-alkylcyclohexane derivative (e.g.,neramexane or a pharmaceutically acceptable salt thereof such asneramexane mesylate) and the additional pharmaceutical agent (e.g.,neramexane or a pharmaceutically acceptable salt thereof such asneramexane mesylate) and the additional pharmaceutical agent (e.g.anticholinergic substances (e.g. mecamylamine, kynurenic acid,d-tubocurarine, hexamethonium, atropine, ipratropium, oxitropium, andtiotropium), antihistamines, (e.g. Diphenhydramine, Loratadine,Desloratadine, Meclizine, Quetiapine, Fexofenadine, Pheniramine,Cetirizine, Promethazine, Cimetidine, Famotidine, Ranitidine,Nizatidine, A-349,821, ABT-239, Ciproxifan, Clobenpropit, Thioperamide,JNJ 7777120, Cromoglicate, Nedocromil), Corticosteroids (e.g.prednisone, cortisone, hydrocortisone), glucocorticoids (e.g.ciclesonide, beclomethasone, budesonide, flunisolide, fluticasone,mometasone, and triamcinolone), Leukotriene modifiers (e.g. montelukast,zafirlukast, pranlukast, and zileuton), Methylxanthines (e.g.theophylline and aminophylline), Omalizumab, Methotrexate and ketotifen)are administered conjointly.

A further aspect of the invention relates to the above-definedderivative or use wherein the 1-amino-alkylcyclohexane derivative (e.g.,neramexane or a pharmaceutically acceptable salt thereof such asneramexane mesylate) and the additional pharmaceutical agent (e.g.,neramexane or a pharmaceutically acceptable salt thereof such asneramexane mesylate) and the additional pharmaceutical agent (e.g.anticholinergic substances (e.g. mecamylamine, kynurenic acid,d-tubocurarine, hexamethonium, atropine, ipratropium, oxitropium, andtiotropium), antihistamines, (e.g. Diphenhydramine, Loratadine,Desloratadine, Meclizine, Quetiapine, Fexofenadine, Pheniramine,Cetirizine, Promethazine, Cimetidine, Famotidine, Ranitidine,Nizatidine, A-349,821, ABT-239, Ciproxifan, Clobenpropit, Thioperamide,JNJ 7777120, Cromoglicate, Nedocromil), Corticosteroids (e.g.prednisone, cortisone, hydrocortisone), glucocorticoids (e.g.ciclesonide, beclomethasone, budesonide, flunisolide, fluticasone,mometasone, and triamcinolone), Leukotriene modifiers (e.g. montelukast,zafirlukast, pranlukast, and zileuton), Methylxanthines (e.g.theophylline and aminophylline), Omalizumab, Methotrexate and ketotifen)are administered in a single formulation.

A further aspect of the invention relates to the above-definedderivative or use wherein the 1-amino-alkylcyclohexane derivative (e.g.,neramexane or a pharmaceutically acceptable salt thereof such asneramexane mesylate) and the additional pharmaceutical agent (e.g.,neramexane or a pharmaceutically acceptable salt thereof such asneramexane mesylate) and the additional pharmaceutical agent (e.g.anticholinergic substances (e.g. mecamylamine, kynurenic acid,d-tubocurarine, hexamethonium, atropine, ipratropium, oxitropium, andtiotropium), antihistamines, (e.g. Diphenhydramine, LoratadineDesloratadine, Meclizine, Quetiapine, Fexofenadine, Pheniramine,Cetirizine, Promethazine, Cimetidine, Famotidine, Ranitidine,Nizatidine, A-349,821, ABT-239, Ciproxifan, Clobenpropit, Thioperamide,JNJ 7777120, Cromoglicate, Nedocromil), Corticosteroids (e.g.prednisone, cortisone, hydrocortisone), glucocorticoids (e.g.ciclesonide, beclomethasone, budesonide, flunisolide, fluticasone,mometasone, and triamcinolone), Leukotriene modifiers (e.g. montelukast,zafirlukast, pranlukast, and zileuton), Methylxanthines (e.g.theophylline and aminophylline), Omalizumab, Methotrexate and ketotifen)are administered in a topical formulation such as a topical rinse-off orleave-on formulation.

A further aspect of the invention relates to the above-definedderivative or use wherein the 1-amino-alkylcyclohexane derivative (e.g.,neramexane or a pharmaceutically acceptable salt thereof such asneramexane mesylate) and the additional pharmaceutical agent (e.g.anticholinergic substances (e.g. mecamylamine, kynurenic acid,d-tubocurarine, hexamethonium, atropine, ipratropium, oxitropium, andtiotropium), antihistamines, (e.g. Diphenhydramine, Loratadine,Desloratadine, Meclizine, Quetiapine, Fexofenadine, Pheniramine,Cetirizine, Promethazine, Cimetidine, Famotidine, Ranitidine,Nizatidine, A-349,821, ABT-239, Ciproxifan, Clobenpropit, Thioperamide,JNJ 7777120, Cromoglicate, Nedocromil), Corticosteroids (e.g.prednisone, cortisone, hydrocortisone), glucocorticoids (e.g.ciclesonide, beclomethasone, budesonide, flunisolide, fluticasone,mometasone, and triamcinolone), Leukotriene modifiers (e.g. montelukast,zafirlukast, pranlukast, and zileuton), Methylxanthines (e.g.theophylline and aminophylline), Omalizumab, Methotrexate and ketotifen)are administered in an oral formulation.

A further aspect of the invention relates to the above-definedderivative or use wherein the 1-amino-alkylcyclohexane derivative (e.g.,neramexane or a pharmaceutically acceptable salt thereof such asneramexane mesylate) and the additional pharmaceutical agent (e.g.anticholinergic substances (e.g. mecamylamine, kynurenic acid,d-tubocurarine, hexamethonium, atropine, ipratropium, oxitropium, andtiotropium), antihistamines, (e.g. Diphenhydramine, Loratadine,Desloratadine, Meclizine, Quetiapine, Fexofenadine, Pheniramine,Cetirizine, Promethazine, Cimetidine, Famotidine, Ranitidine,Nizatidine, A-349,821, ABT-239, Ciproxifan, Clobenpropit, Thioperamide,JNJ 7777120, Cromoglicate, Nedocromil), Corticosteroids (e.g.prednisone, cortisone, hydrocortisone), glucocorticoids (e.g.ciclesonide, beclomethasone, budesonide, flunisolide, fluticasone,mometasone, and triamcinolone), Leukotriene modifiers (e.g. montelukast,zafirlukast, pranlukast, and zileuton), Methylxanthines (e.g.theophylline and aminophylline), Omalizumab, Methotrexate and ketotifen)are administered systemically.

A further aspect of the invention relates to a pharmaceuticalcomposition for the treatment of mast cell mediated diseases comprisinga therapeutically effective amount of a 1-amino-alkylcyclohexanederivative (e.g., neramexane or a pharmaceutically acceptable saltthereof such as neramexane mesylate), and, optionally, at least onepharmaceutically acceptable carrier or excipient.

A further aspect of the invention relates to a pharmaceuticalcomposition for the treatment of mast cell mediated diseases comprisinga therapeutically effective amount of a 1-amino-alkylcyclohexanederivative (e.g., neramexane or a pharmaceutically acceptable saltthereof such as neramexane mesylate) in an immediate or modified releaseformulation.

A further aspect of the invention relates to a pharmaceuticalcomposition for the treatment of mast cell mediated diseases comprisinga therapeutically effective amount of a 1-amino-alkylcyclohexanederivative (e.g., neramexane or a pharmaceutically acceptable saltthereof such as neramexane mesylate) in a topical formulation.

A further aspect of the invention relates to a pharmaceuticalcomposition for the treatment of mast cell mediated diseases comprisinga therapeutically effective amount of a 1-amino-alkylcyclohexanederivative (e.g., neramexane or a pharmaceutically acceptable saltthereof such as neramexane mesylate) in an oral formulation.

A further aspect of the invention relates to a pharmaceuticalcomposition comprising a therapeutically effective amount of a1-amino-alkylcyclohexane derivative (e.g., neramexane or apharmaceutically acceptable salt thereof such as neramexane mesylate) incombination with at least one additional pharmaceutical agent (e.g.anticholinergic substances (e.g. mecamylamine, kynurenic acid,d-tubocurarine, hexamethonium, atropine, ipratropium, oxitropium, andtiotropium), antihistamines, (e.g. Diphenhydramine, Loratadine,Desloratadine, Meclizine, Quetiapine, Fexofenadine, Pheniramine,Cetirizine, Promethazine, Cimetidine, Famotidine, Ranitidine,Nizatidine, A-349,821, ABT-239, Ciproxifan, Clobenpropit, Thioperamide,JNJ 7777120, Cromoglicate, Nedocromil), Corticosteroids (e.g.prednisone, cortisone, hydrocortisone), glucocorticoids (e.g.ciclesonide, beclomethasone, budesonide, flunisolide, fluticasone,mometasone, and triamcinolone), Leukotriene modifiers (e.g. montelukast,zafirlukast, pranlukast, and zileuton), Methylxanthines (e.g.theophylline and aminophylline), Omalizumab, Methotrexate and ketotifen)which has been shown to be effective in treating mast cell mediateddiseases and, optionally, at least one pharmaceutically acceptablecarrier or excipient.

A further aspect of the invention relates to a pharmaceuticalcomposition comprising a therapeutically effective amount of a1-amino-alkylcyclohexane derivative (e.g., neramexane or apharmaceutically acceptable salt thereof such as neramexane mesylate) incombination with at least one additional pharmaceutical agent (e.g.anticholinergic substances (e.g. mecamylamine, kynurenic acid,d-tubocurarine, hexamethonium, atropine, ipratropium, oxitropium, andtiotropium), antihistamines, (e.g. Diphenhydramine, Loratadine,Desloratadine, Meclizine, Quetiapine, Fexofenadine, Pheniramine,Cetirizine, Promethazine, Cimetidine, Famotidine, Ranitidine,Nizatidine, A-349,821, ABT-239, Ciproxifan, Clobenpropit, Thioperamide,JNJ 7777120, Cromoglicate, Nedocromil), Corticosteroids (e.g.prednisone, cortisone, hydrocortisone), glucocorticoids (e.g.ciclesonide, beclomethasone, budesonide, flunisolide, fluticasone,mometasone, and triamcinolone), Leukotriene modifiers (e.g. montelukast,zafirlukast, pranlukast, and zileuton), Methylxanthines (e.g.theophylline and aminophylline), Omalizumab, Methotrexate and ketotifen)which has been shown to be effective in treating mast cell mediateddiseases and, optionally, at least one pharmaceutically acceptablecarrier or excipient in the form of an topical or oral formulation.

A further aspect of the invention relates to a method of treating orpreventing mast cell mediated diseases in a subject in need thereof,comprising administering an effective amount of a1-amino-alkylcyclohexane derivative.

A further aspect of the invention relates to such a method wherein the1-amino-alkylcyclohexane derivative is neramexane or a pharmaceuticallyacceptable salt thereof.

A further aspect of the invention relates to such a method wherein the1-amino-alkylcyclohexane derivative is neramexane mesylate.

A further aspect of the invention relates to such a method whereinneramexane mesylate is administered in a range from about 5 mg to about150 mg/day.

A further aspect of the invention relates to such a method whereinneramexane mesylate is administered in a range from about 5 mg to about100 mg/day.

A further aspect of the invention relates to such a method whereinneramexane mesylate is administered at about 5 mg to about 75 mg/day.

A further aspect of the invention relates to such a method whereinneramexane mesylate is administered at about 50 mg/day.

A further aspect of the invention relates to such a method whereinneramexane mesylate is administered at about 75 mg/day.

A further aspect of the invention relates to a method of treating orpreventing mast cell mediated diseases in a subject in need thereof,comprising administering an effective amount of a1-amino-alkylcyclohexane derivative, wherein the1-amino-alkylcyclohexane derivative is administered once a day, twice aday (b.i.d.), or three times a day.

A further aspect of the invention relates to a method of treating orpreventing mast cell mediated diseases in a subject in need thereof,comprising administering an effective amount of a1-amino-alkylcyclohexane derivative, wherein the1-amino-alkylcyclohexane derivative is administered in a topicalformulation.

A further aspect of the invention relates to such a method wherein the1-amino-alkylcyclohexane derivative is administered between 0.1 and 99%by weight of the formulation.

A further aspect of the invention relates to a method of treating orpreventing mast cell mediated diseases in a subject in need thereof,comprising administering an effective amount of a1-amino-alkylcyclohexane derivative, wherein the1-amino-alkylcyclohexane derivative is administered in an oralformulation.

A further aspect of the invention relates to a method of treating orpreventing mast cell mediated diseases, wherein the mast cell mediateddisease is not psoriasis, in a subject in need thereof, comprisingadministering an effective amount of a 1-amino-alkylcyclohexanederivative.

A further aspect of the invention relates to a method of treating orpreventing a mast cell mediated disease selected from urticaria, atopicdermatitis, psoriasis, pruritus, asthma, rhinitis, mastocytosis,conjunctivitis and keratoconjunctivitis in a subject in need thereof,comprising administering an effective amount of a1-amino-alkylcyclohexane derivative.

A further aspect of the invention relates to a method of treating orpreventing atopic dermatitis in a subject in need thereof, comprisingadministering an effective amount of a 1-amino-alkylcyclohexanederivative.

A further aspect of the invention relates to a method of treating orpreventing a food allergy in a subject in need thereof, comprisingadministering an effective amount of a 1-amino-alkylcyclohexanederivative.

A further aspect of the invention relates to a method of treating orpreventing a mast cell mediated disease selected from urticaria, atopicdermatitis, psoriasis, pruritus, asthma, rhinitis, mastocytosis,conjunctivitis and keratoconjunctivitis in a subject in need thereof,comprising administering an effective amount of a1-amino-alkylcyclohexane derivative, wherein the1-amino-alkylcyclohexane derivative is administered in a topicalformulation.

A further aspect of the invention relates to a pharmaceuticalcomposition comprising a therapeutically effective amount of a1-amino-alkylcyclohexane derivative in combination with an additionalpharmaceutical agent which has been shown to be effective for thetreatment or the prevention of mast cell mediated diseases and,optionally, at least one pharmaceutically acceptable carrier orexcipient.

A further aspect of the invention relates to such a pharmaceuticalcomposition wherein the 1-amino-alkylcyclohexane derivative isneramexane or a pharmaceutically acceptable salt thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the effects of neramexane on mast cell degranulation invitro.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the term mast cell mediated diseases includes urticaria,atopic dermatitis, psoriasis, pruritus, asthma, rhinitis, mastocytosis,conjunctivitis, and keratoconjunctivitis.

As used herein, the term mast cell mediated diseases includes also foodallergies.

As used herein, the term urticaria includes allergic urticaria andnon-allergic urticaria.

As used herein, the term atopic dermatitis includes atopic eczema

As used herein, the term psoriasis includes psoriasis vulgaris, plaquepsoriasis, flexural psoriasis, inverse psoriasis, guttate psoriasis,pustular psoriasis, nail psoriasis, erythrodermic psoriasis andpsoriatic arthritis.

As used herein, the term asthma includes asthma bronchiale, allergic andnon-allergic asthma.

As used herein, the term rhinitis includes allergic rhinitis (e.gseasonal, perennial, and occupational rhinitis) and non allergicrhinitis (e.g. eosinophils, autonomic, hormonal, drug-induced, atrophic,and gustatory rhinitis) and infective rhinitis.

As used herein, the term mastocytosis includes cutaneous mastocytosisand systemic mastocytosis.

As used herein, the term food allergy includes an immune response to afood protein such as a dairy allergy, an egg allergy, a peanut allergy,a tree nut allergy, a seafood allergy, a shellfish allergy, a soyallergy, and a wheat allergy or a combination thereof.

As used herein, the terms mecamylamine, kynurenic acid, d-tubocurarine,hexamethonium, atropine, ipratropium, oxitropium, tiotropium,Diphenhydramine, Loratadine, Desloratadine, Meclizine, Quetiapine,Fexofenadine, Pheniramine, Cetirizine, Promethazine, Cimetidine,Famotidine, Ranitidine, Nizatidine, A-349,821, ABT-239, Ciproxifan,Clobenpropit, Thioperamide, JNJ 7777120, Cromoglicate, Nedocromil,prednisone, cortisone, hydrocortisone, ciclesonide, beclomethasone,budesonide, flunisolide, fluticasone, mometasone, triamcinolone,montelukast, zafirlukast, pranlukast, zileuton, Methylxanthines,theophylline, aminophylline, Omalizumab, Methotrexate, and ketotifeninclude optical isomers, diastereomers, enantiomers, hydrates,pharmaceutically acceptable salts, and mixtures thereof, respectively.

As used herein, the term “subject” encompasses mammals including animalsand humans.

The term 1-amino-alkylcyclohexane derivative is used herein to describea 1-amino-alkylcyclohexane or a compound derived from1-amino-alkylcyclohexane, e.g., pharmaceutically acceptable salts of1-amino-alkylcyclohexanes.

The 1-amino-alkylcyclohexane derivatives of the present invention may berepresented by the general formula (I):

wherein R* is —(CH₂)_(n)—(CR⁶R⁷)_(m)—NR⁸R⁹wherein n+m=0, 1, or 2wherein R¹ through R⁷ are independently selected from the groupconsisting of hydrogen and C₁₋₆alkyl, wherein R⁸ and R⁹ areindependently selected from the group consisting of hydrogen andC₁₋₆alkyl or together represent lower-alkylene —(CH₂)_(x)— wherein x is2 to 5, inclusive, and optical isomers, enantiomers, hydrates, andpharmaceutically-acceptable salts thereof.

Non-limiting examples of the 1-amino-alkylcyclohexanes used according tothe present invention include:

-   1-amino-1,3,5-trimethylcyclohexane,-   1-amino-1(trans),3(trans),5-trimethylcyclohexane,-   1-amino-1(cis),3(cis),5-trimethylcyclohexane,-   1-amino-1,3,3,5-tetramethylcyclohexane,-   1-amino-1,3,3,5,5-pentamethylcyclohexane (neramexane),-   1-amino-1,3,5,5-tetramethyl-3-ethylcyclohexane,-   1-amino-1,5,5-trimethyl-3,3-diethylcyclohexane,-   1-amino-1,5,5-trimethyl-cis-3-ethylcyclohexane,-   1-amino-(1S,5S)cis-3-ethyl-1,5,5-trimethylcyclohexane,-   1-amino-1,5,5-trimethyl-trans-3-ethylcyclohexane,-   1-amino-(1R,5S)trans-3-ethyl-1,5,5-trimethylcyclohexane,    1-amino-1-ethyl-3,3,5,5-tetramethylcyclohexane,-   1-amino-1-propyl-3,3,5,5-tetramethylcyclohexane,-   N-methyl-1-amino-1,3,3,5,5-pentamethylcyclohexane,-   N-ethyl-1-amino-1,3,3,5,5-pentamethyl-cyclohexane,-   N-(1,3,3,5,5-pentamethylcyclohexyl)pyrrolidine,-   3,3,5,5-tetramethylcyclohexylmethylamine,-   1-amino-1-propyl-3,3,5,5-tetramethylcyclohexane,-   1 amino-1,3,3,5(trans)-tetramethylcyclohexane (axial amino group),-   3-propyl-1,3,5,5-tetramethylcyclohexylamine semihydrate,-   1-amino-1,3,5,5-tetramethyl-3-ethylcyclohexane,-   1-amino-1,3,5-trimethylcyclohexane,-   1-amino-1,3-dimethyl-3-propylcyclohexane,-   1-amino-1,3(trans),5(trans)-trimethyl-3(cis)-propylcyclohexane,-   1-amino-1,3-dimethyl-3-ethylcyclohexane,-   1-amino-1,3,3-trimethylcyclohexane,-   cis-3-ethyl-1(trans)-3(trans)-5-trimethylcyclohexamine,-   1-amino-1,3(trans)-dimethylcyclohexane,-   1,3,3-trimethyl-5,5-dipropylcyclohexylamine,-   1-amino-1-methyl-3(trans)-propylcyclohexane,-   1-methyl-3(cis)-propylcyclohexylamine,-   1-amino-1-methyl-3(trans)-ethylcyclohexane,-   1-amino-1,3,3-trimethyl-5(cis)-ethylcyclohexane,-   1-amino-1,3,3-trimethyl-5(trans)-ethylcyclohexane,-   cis-3-propyl-1,5,5-trimethylcyclohexylamine,-   trans-3-propyl-1,5,5-trimethylcyclohexylamine,-   N-ethyl-1,3,3,5,5-pentamethylcyclohexylamine,-   N-methyl-1-amino-1,3,3,5,5-pentamethylcyclohexane,-   1-amino-1-methylcyclohexane,-   N,N-dimethyl-1-amino-1,3,3,5,5-pentamethylcyclohexane,-   2-(3,3,5,5-tetramethylcyclohexyl)ethylamine,-   2-methyl-1-(3,3,5,5-tetramethylcyclohexyl)propyl-2-amine,-   2-(1,3,3,5,5-pentamethylcyclohexyl-1)-ethylamine semihydrate,-   N-(1,3,3,5,5-pentamethylcyclohexyl)-pyrrolidine,-   1-amino-1,3(trans),5(trans)-trimethylcyclohexane,-   1-amino-1,3(cis),5(cis)-trimethylcyclohexane,-   1-amino-(1R,5S)trans-5-ethyl-1,3,3-trimethylcyclohexane,-   1-amino-(1S,5S)cis-5-ethyl-1,3,3-trimethylcyclohexane,-   1-amino-1,5,5-trimethyl-3(cis)-isopropyl-cyclohexane,-   1-amino-1,5,5-trimethyl-3(trans)-isopropyl-cyclohexane,-   1-amino-1-methyl-3(cis)-ethyl-cyclohexane,-   1-amino-1-methyl-3(cis)-methyl-cyclohexane,-   1-amino-5,5-diethyl-1,3,3-trimethyl-cyclohexane,-   1-amino-1,3,3,5,5-pentamethylcyclohexane,-   1-amino-1,5,5-trimethyl-3,3-diethylcyclohexane,-   1-amino-1-ethyl-3,3,5,5-tetramethylcyclohexane,-   N-ethyl-1-amino-1,3,3,5,5-pentamethylcyclohexane,-   N-(1,3,5-trimethylcyclohexyl)pyrrolidine or piperidine,-   N-[1,3(trans),5(trans)-trimethylcyclohexyl]pyrrolidine or    piperidine,-   N-[1,3(cis),5(cis)-trimethylcyclohexyl]pyrrolidine or piperidine,-   N-(1,3,3,5-tetramethylcyclohexyl)pyrrolidine or piperidine,-   N-(1,3,3,5,5-pentamethylcyclohexyl)pyrrolidine or piperidine,-   N-(1,3,5,5-tetramethyl-3-ethylcyclohexyl)pyrrolidine or piperidine,-   N-(1,5,5-trimethyl-3,3-diethylcyclohexyl)pyrrolidine or piperidine,-   N-(1,3,3-trimethyl-cis-5-ethylcyclohexyl)pyrrolidine or piperidine,-   N-[(1S,5S)cis-5-ethyl-1,3,3-trimethylcyclohexyl]pyrrolidine or    piperidine,-   N-(1,3,3-trimethyl-trans-5-ethylcyclohexyl)pyrrolidine or    piperidine,-   N-[(1R,5S)trans-5-ethyl,3,3-trimethylcyclohexyl]pyrrolidine or    piperidine,-   N-(1-ethyl-3,3,5,5-tetramethylyclohexyl)pyrrolidine or piperidine,-   N-(1-propyl-3,3,5,5-tetramethylcyclohexyl)pyrrolidine or piperidine,-   N-(1,3,3,5,5-pentamethylcyclohexyl)pyrrolidine,    and optical isomers, diastereomers, enantiomers, hydrates, their    pharmaceutically acceptable salts, and mixtures thereof.

1-Amino-alkylcyclohexane derivatives (e.g., neramexane,1-amino-1,3,3,5,5-pentamethylcyclohexane) are disclosed in U.S. Pat.Nos. 6,034,134 and 6,071,966. 1-Amino-alkylcyclohexane derivatives(e.g., neramexane) may be used according to the invention in the form ofany of pharmaceutically acceptable salts, solvates, isomers, conjugates,and prodrugs, any references to 1-amino-alkylcyclohexane derivatives(e.g., neramexane) in this description should be understood as alsoreferring to such salts, solvates, isomers, conjugates, and prodrugs.

Pharmaceutically acceptable salts include, but are not limited to, acidaddition salts, such as those made with hydrochloric, methylsulfonic,hydrobromic, hydroiodic, perchloric, sulfuric, nitric, phosphoric,acetic, propionic, glycolic, lactic, pyruvic, malonic, succinic,fumaric, tartaric, citric, benzoic, carbonic, cinnamic, mandelic,methanesulfonic, ethanesulfonic, hydroxyethanesulfonic,benezenesulfonic, p-toluene sulfonic, cyclohexanesulfamic, salicylic,p-aminosalicylic, 2-phenoxybenzoic, and 2-acetoxybenzoic acid. All ofthese salts (or other similar salts) may be prepared by conventionalmeans. The nature of the salt is not critical, provided that it isnon-toxic and does not substantially interfere with the desiredpharmacological activity.

The term “analog” or “derivative” is used herein in the conventionalpharmaceutical sense, to refer to a molecule that structurally resemblesa reference molecule (such as neramexane), but has been modified in atargeted and controlled manner to replace one or more specificsubstituents of the reference molecule with an alternate substituent,thereby generating a molecule which is structurally similar to thereference molecule. Synthesis and screening of analogs (e.g., usingstructural and/or biochemical analysis), to identify slightly modifiedversions of a known compound which may have improved or biased traits(such as higher potency and/or selectivity at a specific targetedreceptor type, greater ability to penetrate mammalian barriers, such ascell membranes, fewer side effects, etc.) is a drug design approach thatis well known in pharmaceutical chemistry.

The term “treat” is used herein to mean to relieve or alleviate at leastone symptom of a disease in a subject. Within the meaning of the presentinvention, the term “treat” also denotes to arrest, delay the onset(i.e., the period prior to clinical manifestation of a disease) and/orreduce the risk of developing or worsening a disease.

The term “therapeutically effective” applied to dose or amount refers tothat quantity of a compound or pharmaceutical composition that issufficient to result in a desired activity upon administration to amammal in need thereof.

The phrase “pharmaceutically acceptable”, as used in connection withcompositions of the invention, refers to molecular entities and otheringredients of such compositions that are physiologically tolerable anddo not typically produce untoward reactions when administered to amammal (e.g., human). The term “pharmaceutically acceptable” may alsomean approved by a regulatory agency of the Federal or a stategovernment or listed in the U.S. Pharmacopeia or other generallyrecognized pharmacopeia for use in mammals, and more particularly inhumans.

The term “carrier” applied to pharmaceutical compositions of theinvention refers to a diluent, excipient, or vehicle with which anactive compound (e.g., neramexane) is administered. Such pharmaceuticalcarriers can be sterile liquids, such as water, saline solutions,aqueous dextrose solutions, aqueous glycerol solutions, and oils,including those of petroleum, animal, vegetable or synthetic origin,such as peanut oil, soybean oil, mineral oil, sesame oil and the like.Suitable pharmaceutical carriers are described e.g. in “Remington'sPharmaceutical Sciences” by A. R. Gennaro, 20^(th) Edition.

The term “about” or “approximately” usually means within 20%,alternatively within 10%, including within 5% of a given value or range.Alternatively, especially in biological systems, the term “about” meanswithin about a log (i.e., an order of magnitude), including within afactor of two of a given value.

Pharmaceutical Formulations and Administration

In conjunction with the methods of the present invention, also providedare pharmaceutical compositions comprising a therapeutically effectiveamount of a 1-amino-alkylcyclohexane derivative (e.g., neramexane). Thecompositions of the invention may further comprise a carrier orexcipient (all pharmaceutically acceptable). The compositions may beformulated for once-a-day administration, twice-a-day administration, orthree times a day administration.

The active ingredient (e.g., neramexane, such as neramexane mesylate) orthe composition of the present invention may be used for the treatmentof at least one of the mentioned disorders, wherein the treatment isadapted to or appropriately prepared for a specific administration asdisclosed herein (e.g., to once-a-day, twice-a-day, or three times a dayadministration). For this purpose the package leaflet and/or the patientinformation contains corresponding information.

The active ingredient (e.g., neramexane, such as neramexane mesylate) orthe composition of the present invention may be used for the manufactureof a medicament for the treatment of at least one of the mentioneddisorders, wherein the medicament is adapted to or appropriatelyprepared for a specific administration as disclosed herein (e.g., toonce-a-day, twice-a-day, or three times a day administration). For thispurpose the package leaflet and/or the patient information containscorresponding information.

According to the present invention, the dosage form of the1-amino-alkylcyclohexane derivative (e.g., neramexane) may be a solid,semisolid, or liquid formulation according to the following.

The 1-amino-alkylcyclohexane derivatives of the present invention (e.g.,neramexane) may be administered orally, topically, parenterally, ormucosally (e.g., buccally, by inhalation, or rectally) in dosage unitformulations containing conventional non-toxic pharmaceuticallyacceptable carriers. In another embodiment for administration topediatric subjects, the 1-amino-alkylcyclohexane derivative may beformulated as a flavored liquid (e.g., peppermint flavor). The1-amino-alkylcyclohexane derivatives of the present invention may beadministered orally in the form of a capsule, a tablet, or the like, oras a liquid formulation or topically as a semi-solid such as anointment, cream, gel, or hydrogel (see Remington's PharmaceuticalSciences, 20^(th) Edition, by A. R. Gennaro).

For oral administration in the form of a tablet or capsule, the1-amino-alkylcyclohexane derivatives of the present invention (e.g.,neramexane) may be combined with non-toxic, pharmaceutically acceptableexcipients such as binding agents (e.g., pregelatinized maize starch,polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g.,lactose, sucrose, glucose, mannitol, sorbitol and other reducing andnon-reducing sugars, microcrystalline cellulose, calcium sulfate, orcalcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc,or silica, steric acid, sodium stearyl fumarate, glyceryl behenate,calcium stearate, and the like); disintegrants (e.g., potato starch orsodium starch glycolate); or wetting agents (e.g., sodium laurylsulphate), coloring and flavoring agents, gelatin, sweeteners, naturaland synthetic gums (such as acacia, tragacanth or alginates), buffersalts, carboxymethylcellulose, polyethyleneglycol, waxes, and the like.

The tablets may be coated with a concentrated sugar solution which maycontain e.g., gum arabic, gelatine, talcum, titanium dioxide, and thelike. Alternatively, the tablets can be coated with a polymer thatdissolves in a readily volatile organic solvent or mixture of organicsolvents. In specific embodiments, neramexane is formulated inimmediate-release (IR) or modified-release (MR) dosage forms. Immediaterelease solid dosage forms permit the release of most or all of theactive ingredient over a short period of time, such as 60 minutes orless, and make rapid absorption of the drug possible (immediate releaseformulations of 1-amino-alkylcyclohexanes such as neramexane aredisclosed in US Published Application Nos. 2006/0002999 and2006/0198884, the subject matter of which is hereby incorporated byreference). Modified release solid oral dosage forms permit thesustained release of the active ingredient over an extended period oftime in an effort to maintain therapeutically effective plasma levelsover similarly extended time intervals and/or to modify otherpharmacokinetic properties of the active ingredient (modified releaseformulations of neramexane are disclosed in US Published Application No.2007/0141148, the subject matter of which is hereby incorporated byreference).

For the formulation of soft gelatin capsules, the1-amino-alkylcyclohexane derivatives of the present invention (e.g.,neramexane) may be admixed with e.g., a vegetable oil or poly-ethyleneglycol. Hard gelatin capsules may contain granules of the activesubstances using either the above mentioned excipients for tablets e.g.,lactose, saccharose, sorbitol, mannitol, starches (e.g., potato starch,corn starch or amylopectin), cellulose derivatives or gelatine. Alsoliquids or semisolids of the drug can be filled into hard gelatinecapsules.

The 1-amino-alkylcyclohexane derivatives of the present invention (e.g.,neramexane) can also be introduced in microspheres or microcapsules,e.g., fabricated from polyglycolic acid/lactic acid (PGLA) (see, e.g.,U.S. Pat. Nos. 5,814,344; 5,100,669 and 4,849,222; PCT Publications No.WO 95/11010 and WO 93/07861). Biocompatible polymers may be used inachieving controlled release of a drug, include for example, polylacticacid, polyglycolic acid, copolymers of polylactic and polyglycolic acid,polyepsilon caprolactone, polyhydroxybutyric acid, polyorthoesters,polyacetals, polyhydropyrans, polycyanoacrylates, and cross-linked oramphipathic block copolymers of hydrogels.

Formulation of the 1-amino-alkylcyclohexane derivatives of the presentinvention in a semi-solid or liquid form may also be used. The1-amino-alkylcyclohexane derivative (e.g., neramexane) may constitutebetween 0.1 and 99% by weight of the formulation, more specificallybetween 0.5 and 20% by weight for formulations intended for injectionand between 0.2 and 50% by weight for formulations suitable for oraladministration.

Formulations of the 1-amino-alkylcyclohexane derivatives of the presentinvention in a semi-solid or liquid form suitable for topicaladministration may also be used. Such formulations include gels, creams,ointments, hydrogels, pastes, emulsions, sprays, solutions, lotions,etc. The 1-amino-alkylcyclohexane derivative (e.g., neramexane) mayconstitute between 0.1 and 99% by weight of the formulation, morespecifically between 0.5% and 50% by weight of the formulation orbetween 1% and 25% by weight of the formulation or between 2% and 20% byweight of the formulation.

In one embodiment of the invention, the 1-amino-alkylcyclohexanederivative (e.g., neramexane) is administered in a modified releaseformulation. Modified release dosage forms provide a means for improvingpatient compliance and for ensuring effective and safe therapy byreducing the incidence of adverse drug reactions. Compared to immediaterelease dosage forms, modified release dosage forms can be used toprolong pharmacologic action after administration, and to reducevariability in the plasma concentration of a drug throughout the dosageinterval, thereby eliminating or reducing sharp peaks.

A modified release form dosage form may comprise a core either coatedwith or containing a drug. The core is then coated with a releasemodifying polymer within which the drug is dispersed. The releasemodifying polymer disintegrates gradually, releasing the drug over time.Thus, the outer-most layer of the composition effectively slows down andthereby regulates the diffusion of the drug across the coating layerwhen the composition is exposed to an aqueous environment, i.e. thegastrointestinal tract. The net rate of diffusion of the drug is mainlydependent on the ability of the gastric fluid to penetrate the coatinglayer or matrix and on the solubility of the drug itself.

In another embodiment of the invention, the 1-amino-alkylcyclohexanederivative (e.g., neramexane) is formulated in an oral, liquidformulation. Liquid preparations for oral administration can take theform of, for example, solutions, syrups, emulsions or suspensions, orthey can be presented as a dry product for reconstitution with water orother suitable vehicle before use. Preparations for oral administrationcan be suitably formulated to give controlled or postponed release ofthe active compound. Oral liquid formulations of1-amino-alkylcyclohexanes, such as neramexane, are described in PCTInternational Application No. PCT/US2004/037026, the subject matter ofwhich is hereby incorporated by reference.

For oral administration in liquid form, 1-amino-alkylcyclohexanederivatives of the present invention (e.g., neramexane) may be combinedwith non-toxic, pharmaceutically acceptable inert carriers (e.g.,ethanol, glycerol, water), suspending agents (e.g., sorbitol syrup,cellulose derivatives or hydrogenated edible fats), emulsifying agents(e.g., lecithin or acacia), non-aqueous vehicles (e.g., almond oil, oilyesters, ethyl alcohol or fractionated vegetable oils), preservatives(e.g., methyl or propyl-p-hydroxybenzoates or sorbic acid), and thelike. Stabilizing agents such as antioxidants (e.g. BHA, BHT, propylgallate, sodium ascorbate, citric acid) can also be added to stabilizethe dosage forms. For example, solutions may contain from about 0.2% toabout 20% by weight of neramexane, with the balance being sugar andmixture of ethanol, water, glycerol and propylene glycol. Optionally,such liquid formulations may contain coloring agents, flavoring agents,sweetening agents and thickening agents, such ascarboxymethyl-cellulose, or other excipients.

In another embodiment, a therapeutically effective amount of a1-amino-alkylcyclohexane derivative (e.g., neramexane) is administeredin an oral solution containing a preservative, a sweetener, asolubilizer, and a solvent. The oral solution may include one or morebuffers, flavorings, or additional excipients. In a further embodiment,a peppermint or other flavoring is added to the neramexane derivativeoral liquid formulation.

For administration by inhalation, 1-amino-alkylcyclohexane derivatives(e.g., neramexane) of the present invention may be convenientlydelivered in the form of an aerosol spray presentation from pressurizedpacks or a nebulizer, with the use of a suitable propellant, e.g.,dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. In thecase of a pressurized aerosol, the dosage unit can be determined byproviding a valve to deliver a metered amount. Capsules and cartridgesof, e.g., gelatin for use in an inhaler or insufflator can be formulatedcontaining a powder mix of the compound and a suitable powder base suchas lactose or starch.

Solutions for parenteral applications by injection may be prepared in anaqueous solution of a water-soluble pharmaceutically acceptable salt ofthe active substances, for example in a concentration of from about 0.5%to about 10% by weight. These solutions may also contain stabilizingagents and/or buffering agents and may conveniently be provided invarious dosage unit ampoules.

The formulations of the invention may be delivered parenterally, i.e.,by intravenous (i.v.), intracerebroventricular (i.c.v.), subcutaneous(s.c.), intraperitoneal (i.p.), intramuscular (i.m.), subdermal (s.d.),or intradermal (i.d.) administration, by direct injection, via, forexample, bolus injection or continuous infusion. Formulations forinjection can be presented in unit dosage form, e.g., in ampoules or inmulti-dose containers, with an added preservative. Alternatively, theactive ingredient may be in powder form for reconstitution with asuitable vehicle, e.g., sterile pyrogen-free water, before use.

The invention also provides a pharmaceutical pack or kit comprising oneor more containers containing a 1-amino-alkylcyclohexane derivative(e.g., neramexane) and, optionally, more of the ingredients of theformulation. In a specific embodiment, neramexane is provided as an oralsolution (2 mg/ml) for administration with the use of a 2 teaspooncapacity syringe (dosage KORC®). Each oral syringe has hatch marks formeasurement, with lines on the right side of the syringe (tip down)representing tsp units, and those on the left representing ml units.

The optimal therapeutically effective amount may be determinedexperimentally, taking into consideration the exact mode ofadministration, from in which the drug is administered, the indicationtoward which the administration is directed, the subject involved (e.g.,body weight, health, age, sex, etc.), and the preference and experienceof the physician or veterinarian in charge.

Dosage units for rectal application may be solutions or suspensions ormay be prepared in the form of suppositories or retention enemascomprising neramexane in a mixture with a neutral fatty base, or gelatinrectal capsules comprising the active substances in admixture withvegetable oil or paraffin oil.

Toxicity and therapeutic efficacy of the compositions of the inventionmay be determined by standard pharmaceutical procedures in experimentalanimals, e.g., by determining the LD₅₀ (the dose lethal to 50% of thepopulation) and the ED₅₀ (the dose therapeutically effective in 50% ofthe population). The dose ratio between therapeutic and toxic effects isthe therapeutic index and it may be expressed as the ratio LD₅₀/ED₅₀.Compositions that exhibit large therapeutic indices are preferred.

Suitable daily doses of the active compounds of the invention intherapeutic treatment of humans are about 0.01-10 mg/kg bodyweight onperoral administration and 0.001-10 mg/kg bodyweight on parenteraladministration. For example, for adults, suitable daily doses ofneramexane (e.g. neramexane mesylate) are within the range from about 5mg to about 150 mg per day, such as from about 5 mg to about 120 mg,from about 5 mg to about 100 mg, or from about 5 mg to about 75 mg, orfrom about 5 mg to about 50 mg, such as 25 mg or 37.5 mg or 50 mg, perday. For example the daily dose may be body weight-adjusted such as 50mg/day up to 90 kg body weight or 75 mg/day for patients with a bodyweight of 90 kg. An equimolar amount of another pharmaceuticallyacceptable salt, a solvate, an isomer, a conjugate, a prodrug or aderivative thereof, such as neramexane hydrochloride, is also suitable.For pediatric subjects aged 4-14, neramexane (e.g. neramexane mesylate)may be administered as an oral, liquid dosage form, at about 0.5 mg/day,up to a maximum dose of 10 mg/day.

The daily doses indicated herein may be administered, for example, asone or two dosing units once, twice or three times per day. Suitabledoses per dosage unit may therefore be the daily dose divided (forexample, equally) between the number of dosage units administered perday, and will thus typically be about equal to the daily dose or onehalf, one third, one quarter or one sixth thereof. Dosages per dosageunit may thus be calculated from each daily dosage indicated herein. Adaily dose of 5 mg, for example may be seen as providing a dose perdosage unit of, for example, about 5 mg, 2.5 mg, 1.67 mg, 1.25 mg and0.83 mg, depending upon the dosing regimen chosen. Correspondingly, adosage of 150 mg per day corresponds to dosages per dosing unit of, forexample, about 150 mg, 75 mg, 50 mg, 37.5 mg, and 25 mg forcorresponding dosing regimens.

Treatment duration may be short-term, e.g., several weeks (for example8-14 weeks), or long-term until the attending physician deems furtheradministration no longer is necessary.

The 1-amino-alkylcyclohexane derivatives of the present invention (e.g.,neramexane) may be administered as a monotherapy, or in combination withanother agent prescribed for the treatment of mast cell mediateddiseases.

The term “combination” applied to active ingredients is used herein todefine a single pharmaceutical composition (formulation) comprising twoactive agents (e.g., a pharmaceutical composition comprising a1-amino-alkylcyclohexane derivative, such as neramexane, and anotheragent prescribed for the treatment of mast cell mediated diseases, suchas anticholinergic substances (e.g. mecamylamine, kynurenic acid,d-tubocurarine, hexamethonium, atropine, ipratropium, oxitropium, andtiotropium), antihistamines, (e.g. Diphenhydramine, Loratadine,Desloratadine, Meclizine, Quetiapine, Fexofenadine, Pheniramine,Cetirizine, Promethazine, Cimetidine, Famotidine, Ranitidine,Nizatidine, A-349,821, ABT-239, Ciproxifan, Clobenpropit, Thioperamide,JNJ 7777120, Cromoglicate, Nedocromil), Corticosteroids (e.g.prednisone, cortisone, hydrocortisone), glucocorticoids (e.g.ciclesonide, beclomethasone, budesonide, flunisolide, fluticasone,mometasone, and triamcinolone), Leukotriene modifiers (e.g. montelukast,zafirlukast, pranlukast, and zileuton), Methylxanthines (e.g.theophylline and aminophylline), Omalizumab, Methotrexate and ketotifen)or two separate pharmaceutical compositions, each comprising an activeagent (e.g. a pharmaceutical composition comprising a1-amino-alkylcyclohexane derivative, such as neramexane, and anotherpharmaceutical composition comprising another agent prescribed for thetreatment of mast cell mediated diseases, such as anticholinergicsubstances (e.g. mecamylamine, kynurenic acid, d-tubocurarine,hexamethonium, atropine, ipratropium, oxitropium, and tiotropium),antihistamines, (e.g. Diphenhydramine, Loratadine, Desloratadine,Meclizine, Quetiapine, Fexofenadine, Pheniramine, Cetirizine,Promethazine, Cimetidine, Famotidine, Ranitidine, Nizatidine, A-349,821,ABT-239, Ciproxifan, Clobenpropit, Thioperamide, JNJ 7777120,Cromoglicate, Nedocromil), Corticosteroids (e.g. prednisone, cortisone,hydrocortisone), glucocorticoids (e.g. ciclesonide, beclomethasone,budesonide, flunisolide, fluticasone, mometasone, and triamcinolone),Leukotriene modifiers (e.g. montelukast, zafirlukast, pranlukast, andzileuton), Methylxanthines (e.g. theophylline and aminophylline),Omalizumab, Methotrexate and ketotifen), to be administered conjointly.

Within the meaning of the present invention, the term “conjointadministration” is used to refer to administration of1-amino-alkylcyclohexane derivative, such as neramexane, and one or moreadditional active agents (e.g. another agent prescribed for thetreatment of mast cell mediated diseases such as anticholinergicsubstances (e.g. mecamylamine, kynurenic acid, d-tubocurarine,hexamethonium, atropine, ipratropium, oxitropium, and tiotropium),antihistamines, (e.g. Diphenhydramine, Loratadine, Desloratadine,Meclizine, Quetiapine, Fexofenadine, Pheniramine, Cetirizine,Promethazine, Cimetidine, Famotidine, Ranitidine, Nizatidine, A-349,821,ABT-239, Ciproxifan, Clobenpropit, Thioperamide, JNJ 7777120,Cromoglicate, Nedocromil), Corticosteroids (e.g. prednisone, cortisone,hydrocortisone), glucocorticoids (e.g. ciclesonide, beclomethasone,budesonide, flunisolide, fluticasone, mometasone, and triamcinolone),Leukotriene modifiers (e.g. montelukast, zafirlukast, pranlukast, andzileuton), Methylxanthines (e.g. theophylline and aminophylline),Omalizumab, Methotrexate and ketotifen) simultaneously in onecomposition, or simultaneously in different compositions, orsequentially. For the sequential administration to be considered“conjoint”, however, 1-amino-alkylcyclohexane derivative, such asneramexane, and the one or more additional agents must be administeredseparated by a time interval which still permits the resultantbeneficial effect for treating mast cell mediated diseases in a mammal.

Examples of Representative Formulations

With the aid of commonly used solvents, auxiliary agents and carriers,active ingredients may be processed into tablets, coated tablets,capsules, drip solutions, suppositories, injection and infusionpreparations, gels, creams, ointments, and the like and can betherapeutically applied by the oral, rectal, parenteral, topical, andadditional routes. Tablets suitable for oral administration may beprepared by conventional tabletting techniques. The following example isgiven by way of illustration only and is not to be construed aslimiting.

Formulation Example 1 Neramexane Mesylate Immediate Release Tablets

The following tables provide the make-up of neramexane immediate releasetablets in 12.5, 25.0, 37.5, and 50.0 mg dosages, including activecomponents, coating agents, and other excipients.

TABLE 1 Neramexane mesylate, 12.5 mg film coated tablets ComponentAmount [mg] Function Neramexane mesylate 12.50 Active pharmaceuticalingredient Cellulose microcrystalline 103.25 Binder Croscarmellosesodium 6.25 Disintegrant Silicon dioxide, colloidal 1.25 Flow promoterTalc 1.25 Glident Magnesium stearate 0.50 Lubricant core weight 125.00Coating (HPMC), Opadry or 5.00 Coating Sepifilm Coat weight 5.00 coatedtablet total weight 130.00

TABLE 2 Neramexane mesylate, 25.0 mg film coated tablets ComponentAmount [mg] Function Neramexane mesylate 25.00 Active pharmaceuticalingredient Cellulose microcrystalline 206.50 Binder Croscarmellosesodium 12.5 Disintegrant Silicon dioxide, colloidal 2.50 Flow promoterTalc 2.50 Glident Magnesium stearate 1.00 Lubricant core weight 250.00Coating (HPMC), Opadry or 10.00 Coating Sepifilm Coat weight 10.00coated tablet total weight 260.00

TABLE 3 Neramexane mesylate, 37.5 mg film coated tablets ComponentAmount [mg] Function Neramexane mesylate 37.50 Active pharmaceuticalingredient Cellulose microcrystalline 309.75 Binder Croscarmellosesodium 18.75 Disintegrant Silicon dioxide, colloidal 3.75 Flow promoterTalc 3.75 Glident Magnesium stearate 1.50 Lubricant core weight 375.00Coating (HPMC), Opadry or 15.00 Coating Sepifilm Coat weight 15.00coated tablet total weight 390.00

TABLE 4 Neramexane mesylate, 50.0 mg film coated tablets ComponentAmount [mg] Function Neramexane mesylate 50.00 Active pharmaceuticalingredient Cellulose microcrystalline 413.00 Binder Croscarmellosesodium 25.00 Disintegrant Silicon dioxide, colloidal 5.00 Flow promoterTalc 5.00 Glident Magnesium stearate 2.00 Lubricant core weight 500.00Coating (HPMC), Opadry or 20.00 Coating Sepifilm Coat weight 20.00coated tablet total weight 520.00

The following tables provide the make-up of Neramexane topicalformulations.

Formulation Example 2

TABLE 5 “Unguentum emulsificans” Description Amount Alcohol cetylicus etstearylicus 30.0 g emulsificans Paraffinum subliquidum 35.0 g Vaselinumalbum 35.0 g

TABLE 6 “Unguentum emulsificans aquosum” containing 1% NeramexaneDescription Amount Neramexane mesylate  1.0 g Unguentum emulsificans30.0 g Aqua purificata 69.0 g

TABLE 7 “Unguentum emulsificans aquosum” containing 20% NeramexaneDescription Amount Neramexane mesylate 20.0 g Unguentum emulsificans30.0 g Aqua purificata 50.0 g

Formulation Example 3

TABLE 8 “Cremor nonionicus emulsificans aquosum” Description AmountAlcohol cetylicus et stearylicus 21.0 g emulsificans nonionicum2-Ethylhexylis lauras 10.0 g Glycerolum 85% 5.0 g Kalium sorbinicum 0.14g Acidum citricum, anhydricum 0.07 g Aqua purificata 63.79 g

TABLE 9 “Cremor nonionicus emulsificans aquosum” containing 1%Neramexane Description Amount Neramexane mesylate  1.0 g Cremornonionicus emulsificans 99.0 g aquosum

TABLE 10 “Cremor nonionicus emulsificans aquosum” containing 10%Neramexane Description Amount Neramexane mesylate 10.0 g Cremornonionicus emulsificans 90.0 g aquosum

Formulation Example 4

TABLE 11 “Macrogoli unguentum” Description Amount Macrogolum 300 50.0 gMacrogolum 1500 50.0 g

TABLE 12 “Macrogoli unguentum” containing 2% Neramexane DescriptionAmount Neramexane mesylate  2.0 g Macrogoli unguentum 98.0 g

TABLE 13 “Macrogoli unguentum” containing 15% Neramexane DescriptionAmount Neramexane mesylate 15.0 g Macrogoli unguentum 85.0 g

Formulation Example 5

TABLE 14 “Linimentum nonionicum aquosum” Description Amount Alcoholcetylicus et stearylicus 10.5 g emulsificans nonionicum 2-Ethylhexylislauras 5.0 g Glycerolum 85% 2.5 g Kalium sorbinicum 0.14 g Acidumcitricum, anhydricum 0.07 g Aqua purificata 81.79 g

TABLE 15 “Linimentum nonionicum aquosum” containing 3% NeramexaneDescription Amount Neramexane mesylate  3.0 g Linimentum nonionicumaquosum 97.0 g

TABLE 16 “Linimentum nonionicum aquosum” containing 12% NeramexaneDescription Amount Neramexane mesylate 12.0 g Linimentum nonionicumaquosum 88.0 g

TABLE 17 “Linimentum nonionicum aquosum” containing 25% NeramexaneDescription Amount Neramexane mesylate 25.0 g Linimentum nonionicumaquosum 75.0 g

EXAMPLES

The following examples illustrate the invention without limiting itsscope.

Example 1 Effects of Neramexane on Acetyl Choline-Induced Mast CellActivation

Neramexane is tested for its ability to inhibit mast cell degranulationin vitro.

Materials and Methods

Cell Culture

The human mast cell line HMC-1 is obtained from J. H. Butterfield(Minnesota, USA) and cultured under standard conditions in RPMI Medium1640 (GIBCO, Karlsruhe, Germany) at 37° C. For functional assays, thecalcium concentration of the medium is adjusted to 1 mM.

Functional Assays

The Mast cell degranulation is monitored by determination of histamineconcentration in the culture medium using a sandwich-ELISA from IBL(Hamburg, Germany).Histamine concentration is determined in untreatedcells, medium without cells, HMC-1 cells treated with calcimycin, (acalcium ionophore,used as positive control). Additional controls tocheck reagibilty of the cells are LPS (lipopolysaccharide) and PMA(phorbol 12-myristate 13-acetate). Histamine concentration is determined10 minutes after addition of the respective substances. Nicotine andcholine are used as stimulus for nAChR, muscarine as stimulus for mAChR,and a combination of acetylcholine and eserine (an acetylcholinesteraseinhibitor) is used as pancholinergic stimulus. Neramexane is tested atconcentrations ranging from 10E-6M to 10E-16M and is added to theculture medium 5 minutes prior to the respective cholinergic stimulus.All experiments are performed twice in quadruplicate.

Evaluation of Data

Statistical analysis is performed using the Wilcoxon sum-of-ranks test(available on www.statpages.net).

In order to determine the sensitivity of mast cells towards cholinergicsignals, the HMC-1 cell line cultured under standard conditions witheither low or high calcium concentrations is used. Using low calcium,the HMC-1 cells remain unresponsive to ACH, nicotine and calcimycine.Elevation of the calcium concentration to 1 mM renders the HMC-1 cellshighly sensitive towards cholinergic stimulation. ACh, choline andnicotine dose-dependently produce mast cell degranulation evidenced byhistamine concentration in the culture supernatant. Nanomolarconcentrations of ACh and nicotine are sufficient to induce completedegranulation. The specificity of the obtained effect may bedemonstrated by preincubation of the HMC-1 cells with anticholinergicsubstances. Neramexane-mesylate inhibits the observed effects inequimolar concentrations and, dose-dependently, even in lowerconcentrations than the respective agonist. No histamine liberation isproduced by addition of muscarine to the culture medium. These resultsare shown in FIG. 1.

Results

Neramexane demonstrates a dose-dependent inhibitory effect on mast celldegranulation. These results indicate that neramexane may be useful intreating mast cell mediated diseases such as urticaria, atopicdermatitis, psoriasis, pruritus, asthma, rhinitis, mastocytosis,conjunctivitis and keratoconjunctivitis.

These results further indicate that neramexane may be useful in treatingmast cell mediated diseases such food allergy.

The present invention is not to be limited in scope by the specificembodiments described herein. Indeed, various modifications of theinvention in addition to those described herein will become apparent tothose skilled in the art from the foregoing description. Suchmodifications are intended to fall within the scope of the appendedclaims.

All patents, applications, publications, test methods, literature, andother materials cited herein are hereby incorporated by reference.

The invention claimed is:
 1. A method of treating a mast cell mediateddisease selected from pruritus, asthma, rhinitis, mastocytosis,conjunctivitis, keratoconjunctivitis, and food allergies, in a subjectin need thereof, comprising administering an effective amount of a1-amino-alkylcyclohexane derivative selected from neramexane andpharmaceutically acceptable salts thereof.
 2. The method according toclaim 1, wherein the 1-amino-alkylcyclohexane derivative is neramexanemesylate.
 3. The method according to claim 2, wherein neramexanemesylate is administered in a range from about 5 mg to about 150 mg/day.4. The method according to claim 2, wherein neramexane mesylate isadministered in a range from about 5 mg to about 100 mg/day.
 5. Themethod according to claim 2, wherein neramexane mesylate is administeredat about 5 mg to about 75 mg/day.
 6. The method according to claim 2,wherein neramexane mesylate is administered at about 50 mg/day.
 7. Themethod according to claim 2, wherein neramexane mesylate is administeredat about 75 mg/day.
 8. The method according to claim 1, wherein the1-amino-alkylcyclohexane derivative is administered once a day, twice aday (b.i.d.), or three times a day.
 9. The method according to claim 1,wherein the 1-amino-alkylcyclohexane derivative is administered in atopical formulation.
 10. The method according to claim 9, wherein the1-amino-alkylcyclohexane derivative is administered between 0.1 and 99%by weight of the formulation.
 11. The method according to claim 1,wherein the 1-amino-alkylcyclohexane derivative is administered in anoral formulation.